Iminosugars counteract the downregulation of the interferon γ receptor by dengue virus

Joanna L Miller,Michelle L Hill,Juliane Brun,Andrew Pountain,Andrew C Sayce,Nicole Zitzmann

doi:10.1016/j.antiviral.2019.104551

Abstract

The antiviral mechanism of action of iminosugars against many enveloped viruses is hypothesized to be a consequence of misfolding of viral N-linked glycoproteins through inhibition of host endoplasmic reticulum α-glucosidase enzymes. Iminosugar treatment of dengue virus (DENV) infection results in reduced secretion of virions and hence lower viral titres in vitro and in vivo. We investigated whether iminosugars might also affect host receptors important in DENV attachment and uptake and immune responses to DENV.Using a primary human macrophage model of DENV infection, we investigated the effects of maturation with IL-4, DENV-infection and treatment with N-butyl-1-deoxynojirimycin (NB-DNJ) or N-(9-methoxynonyl)-1-DNJ (MON-DNJ) on expression of 11 macrophage receptors.Whereas iminosugars did not affect surface expression of any of the receptors examined, DENV infection significantly reduced surface IFNγ receptor amongst other changes to total receptor expression. This effect required infectious DENV and was reversed by iminosugar treatment. Treatment also affected signalling of the IFNγ receptor and TNFα receptor. In addition, iminosugars reduced ligand binding to the carbohydrate receptor-binding domain of the mannose receptor. This work demonstrates that iminosugar treatment of primary macrophages affects expression and functionality of some key glycosylated host immune receptors important in the dengue life cycle.

Highlights

The antiviral mechanism of action of iminosugars against many enveloped viruses is hypothesized to be a consequence of misfolding of viral N-linked glycoproteins through inhibition of host endoplasmic reticulum αglucosidase enzymes
The major mechanism of iminosugar antiviral activity is believed to be misfolding of viral N-linked glycoproteins through the competitive inhibition of host endoplasmic reticulum (ER) α-glucosidases I and II (Miller et al, 2018) and treatment with iminosugars leads to reduced secretion and infectivity of dengue virions (Sayce et al, 2010, 2016)
Using an established model system in which MDMΦ susceptibility to dengue virus (DENV) infection is enhanced by pre-treatment with IL-4 (Miller et al, 2008) we evaluated the effects of IL-4 treatment, DENV infection, and iminosugar treatment on the expression and function of important macrophage-expressed receptors

Summary

Introduction

The antiviral mechanism of action of iminosugars against many enveloped viruses is hypothesized to be a consequence of misfolding of viral N-linked glycoproteins through inhibition of host endoplasmic reticulum αglucosidase enzymes. This work demonstrates that iminosugar treatment of primary macrophages affects expression and functionality of some key glycosylated host immune receptors important in the dengue life cycle. We investigated whether iminosugar treatment leads to changes in the expression, cellular distribution and functionality of key host-cell receptors as part of the antiviral effect.

Results

Conclusion